EP2611471B1 - Matériau composite à base de chitine de grande résistance et son procédé de fabrication - Google Patents
Matériau composite à base de chitine de grande résistance et son procédé de fabrication Download PDFInfo
- Publication number
- EP2611471B1 EP2611471B1 EP11822477.3A EP11822477A EP2611471B1 EP 2611471 B1 EP2611471 B1 EP 2611471B1 EP 11822477 A EP11822477 A EP 11822477A EP 2611471 B1 EP2611471 B1 EP 2611471B1
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- EP
- European Patent Office
- Prior art keywords
- protein
- carbohydrate
- layer
- composite material
- chitosan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Definitions
- the present invention is directed to an organic composite material formed from carbohydrates and proteins. More specifically, the invention relates to a composite biocompatible material formed from layers of Chitosan and proteins, such as Fibroin, having superior strength and energy-dissipating properties.
- Chitin is the second most abundant polymer on earth after cellulose, it is common waste in seafood factories and (as a natural polymer) it is biodegradable. However its processing in the laboratory for fabrication produce a hydrogel material with poor mechanical properties.
- Chitin is a broadly employed polymer in nature. It is found in the walls of fungi, in mollusk shells and the exoskeleton of arthropods. It provides many structural uses due to its mechanical properties. Many attempts have carried out to employ the polymer as a substitute of current synthetic plastics; however it has not been possible to reproduce its exceptional natural properties in the lab. The lack of success results from the failure to appreciate the important structural role played by chitin-associated proteins that are present within natural structures, and the laminar microarchitecture of naturally occurring materials produced by living organisms.
- the main protein present both in the mollusk shells and the arthropods exoskeleton, which plays a fundamental role in the structural integrity of the shell, has an amino acid sequence similar to that of silk fibroin.
- Chitin and protein (such as silk fibroin) blends have been produced in the prior art by the simple mixing of both materials in solution. These processes are intent on producing consistent mixtures of Chitin/Chitosan and silk fibroin by mixing both polymers in solution and casting the mixture. That approach does not yield any improvement in the mechanical properties of mixture over the components, and typically produces an even weaker material due to the interaction of both polymers, which interferes with each other's molecular and crystal structure.
- a wound dressing comprising a layered structure of chitosan and collagen is disclosed in EP0753313 A1 .
- Silk Fibroin is well known polymer material. Silk provides an important set of material options for biomaterials and tissue engineering because of the impressive mechanical properties, biocompatibility and biodegradability.
- Silk polymer and Silk Fibroin includes silkworm fibroin and insect or spider silk protein ( Lucas et al., Adv. Protein Chem 13: 107-242 (1958 )).
- fibroin is obtained from a solution containing a dissolved silkworm silk or spider silk.
- fibroin polymer (or protein) from silk has been treated to substantially remove sericin.
- the silkworm silk protein is obtained, for example, from Bombyx mori
- the spider silk is obtained, for example, from Nephila clavipes.
- silk proteins suitable for use in the present invention can be obtained from a solution containing a genetically engineered silk, such as from bacteria, yeast, mammalian cells, transgenic animals or transgenic plants. See, for example, WIPO Publication No. WO 1997/108315 and US Patent 5,245,012 .
- Silk fibroin has excellent film-forming capabilities and is also compatible for use in the human body.
- Silk fibroin films without further manipulation or treatment, are soluble in water because of dominating random coil protein structures.
- the structural features of the protein can be transformed from random coil to beta-sheet structure by several treatments, including mechanical stretching, immersion in polar organic solvents, or curing in water vapor.
- use of highly concentrated silk solutions is also known to promote beta-sheet transition from random coils. This structural transition results in aqueous insolubility, thus providing options for the use of the material in a range of biomedical and other applications.
- Silk Fibroin films tend, over time, to become stiff and brittle in the dry state, however, exhibiting impressive tensile strength but low ductility. Further, dissolved Silk Fibroin can be mixed with particulates to produce a homogeneous mixture that can be formed into implantable structures. Methods of making silk polymer structures and Silk Fibroin films are shown in WIPO Publication Nos. WO 2009/0100280 and WO 2010/0042798 .
- the invention relates to the process, as defined by claim 5, for the formation of complex 3D structures with a carbohydrate polymer, i.e. chitin or chitosan, with high control of shape, topography and material properties, and the resulting composite material.
- a carbohydrate polymer i.e. chitin or chitosan
- the resulting composite material has enhanced mechanical strength properties significantly greater than, and not predicted by, any of component materials.
- One object of the invention is to provide a method of fabricating a composite material formed from layers of a carbohydrate based polymer and a protein.
- a composite material formed from layers of a Chitin-based material and a protein is provided.
- Another object of the invention is to provide a method of fabricating a composite material formed from layers of a carbohydrate based polymer and a Fibroin. For example, a method of fabricating a composite material formed from layers of Chitin-based material and Fibroin.
- Another object of the invention is to provide a composite material formed from a carbohydrate based polymer and a protein having superior mechanical properties as compared to its component materials.
- a composite material formed form a Chitin-based material and a protein having superior mechanical properties as compared to its component materials.
- Another object of the invention is to provide a composite material formed from Chitosan and Fibroin having superior mechanical properties as compared to its component materials.
- Another object of the invention is to provide a composite material formed from a carbohydrate based polymer and a protein having adjustable mechanical properties.
- a composite material formed from a Chitin-based material and a protein having adjustable flexibility properties is provided.
- Another object of the invention is to provide a composite material formed from Chitosan and a protein having adjustable mechanical properties.
- Another object of the invention is to provide a composite material formed from Chitosan and a protein that is biocompatible and biodegradable but stable in the presence of moisture.
- the present invention relates to a composite material as defined by claims 1 and 13.
- complex 3D structures with high control of shape, topography and material properties can be fabricated from the resulting composite material.
- the composite material has the structure [(protein-layer) x :[(carbohydrate-layer) y :(protein-layer) z ] m ] n , wherein m, n, y, and z are independently an integer equal to or greater than 1; and x is 0 or an integer equal to or greater than 1.
- n, m, y, and z are independently an integer from 1 to 10 6 .
- each of m, n, y and z can be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
- x can be 0 or an integer from 1 to 10 6 .
- x can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20
- the composite material comprises one or more of layers of carbohydrate-layer:protein-layer, e.g., m is 1, n is 1 to 10 6 , x is 0, y is 1, and z is 1, and the composite material has the structure [carbohydrate-layer:protein-layer]n.
- m is 1; n is 1, 2, 3, 4, 5, 6, 7, 8, or 9; x is 0; y is 1; and z is 1.
- the composite material comprises one carbohydrate-layer and one protein-layer, e.g., m, n, y, and z are 1 and x is 0, and the composite material has the structure carbohydrate-layer:protein-layer.
- the composite material comprises three carbohydrate-layers and three protein-layers, e.g., m, y, and z are 1; x is 0; and n is 3, and the composite material has the structure [carbohydrate-layer:protein-layer] 3 .
- the outer most layer of the composite material is a protein-layer, e.g., m is 1 to 10 6 and n, x, y, and z are all 1, and the composite material has the structure protein-layer: (carbohydrate-layer:protein-layer)m.
- the composite material comprises one carbohydrate-layer and two protein-layers, e.g. m, n, x, y, and z are all one and the composite material has the structure protein-layer:carbohydrate-layer:protein-layer.
- the composite material comprises one carbohydrate-layer and two or more protein-layers, e.g., m is 1, n is 1 to 10 6 , x is 0, y is 1, and z is 2 to 10 6 , and the composite material has the structure [carbohydrate-layer:(protein-layer)z]n.
- n is 1, x is 0, y is 1, and z is 2 to 10 6
- the composite material has the structure carbohydrate-layer:(protein-layer)z.
- z is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- the composite material has the structure [(carbohydrate-layer) p :[(protein-layer) q :(carbohydrate-layer) r ] t ] u , wherein p, q, r, t, and u are independently an integer equal to or greater than 1.
- p, q, r, t, and u are independently an integer from 1 to 10 6 .
- p, q, r, t, and u are independently, 1, 2, 3, 4, 5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
- outer most layer of the composite material is a carbohydrate layer, e.g., p, q, r, and u are 1 and t is 1 to 10 6 , and the composite material has the structure carbohydrate-layer:[protein-layer:carbohydrate-layer] t .
- the composite material comprises two carbohydrate-layer and one protein-layers, e.g. p, q, r, t and u are all 1, and the composite material has the structure carbohydrate-layer:protein-layer: carbohydrate-layer.
- the carbohydrate and the protein layers can be coextensive with each other or not coextensive.
- full surface of the carbohydrate layer can be coated with the protein layer or only a part of the surface of the carbohydrate layer can be coated with the protein layer.
- the sequential modification of the component carbohydrate based materials and the fabrication of composite structure with proteins can provide for the improvement of specific characteristics.
- the resulting composite material has mechanical strength properties significantly greater than any of the component.
- the mechanical strength of the composite material of the invention is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least greater than the mechanical strength of any one of the component materials.
- the mechanical strength of the composite material of the invention is at least 1.2-fold, at least 1.5-fold, at least 10.75-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least greater than the total mechanical strength of the component materials.
- the composite material of the invention has very low density.
- the density of the composite material is less than 2 g/cm 3 , less than 1.9 g/cm 3 , less than 1.8 g/cm 3 , less than 1.7 g/cm 3 , less than 1.6 g/cm 3 , less than 1.5 g/cm 3 , less than 1.4 g/cm 3 , less than 1.3 g/cm 3 , less than 1.2 g/cm 3 , less than 1.1 g/cm 3 , less than 1 g/cm 3 , less than 0.9 g/cm 3 , less than 0.8 g/cm 3 , less than 0.7 g/cm 3 , less than 0.6 g/cm 3 , less than 0.5 g/cm 3 , less than 0.4 g/cm 3 , less than 0.3 g/cm 3 , less than 0.2 g/cm 3 , less than 0.1
- Density of the composite material can be calculated as described in the ASTM specification D792-00.
- W a is the weight of the specimen when hung in the air
- W w is the weight of the partly immersed wire holding the specimen
- W b is the weight of the specimen when immersed fully in distilled water, along with the partly immersed wire holding the specimen
- ⁇ water is the density in g/cm 3 of the distilled water at testing temperature (for example 0.9975 g/cm 3 at 23 °C). While the above is discussed in relation to water, other liquids can be used in place of water.
- the density-gradient techniques for measuring the density of plastics can be employed as described in ASTM specification D1505.
- Density of the composite material can be determined at any suitable temperature and pressure. In some embodiments, density of the composite material is determined at a temperature in the range of 0°C to 25°C. For example, density can be determined at 0°C, 5°C, 10°C, 15°C, 20°C, or 25°C. In some embodiments, density of the composite material is determined at a pressure of 100kPa or 101.325kPa.
- density of the composite material is at standard condition for temperature and pressure.
- the standard condition for temperature and pressure can be those as defined by the International Union of Pure and Applied Chemistry (IUPAC) or the National Institute of Standards and Technology (NIST).
- IUPAC International Union of Pure and Applied Chemistry
- NIST National Institute of Standards and Technology
- the current version of IUPAC's standard is a temperature of 0 °C and an absolute pressure of 100 kPa
- NIST's version is a temperature of 20 °C and an absolute pressure of 101.325 kPa.
- density is measured at 0°C and 100kPa, at 0°C and 101.325kPa, at 15°C and 101.325kPa, at 20°C and 101.325kPa, at 25°C and 101.325kPa, at 25°C and 100kPa, at 20°C and 100kPa, at 15°C and 100kPa, or at 20°C and 101.3kPa.
- the composite material comprises an outer waterproof coating.
- waterproof' refers to a barrier against both liquid and gaseous water (i.e., against both liquid water and water vapor).
- the waterproof coating has a permeability of less than less than 1 as determined by the Water Vapor Transmission Test ASTME96.
- Exemplary water-repelling materials include, but are not limited to, parylene, polydimethylsiloxane, polyethylene, polyvinyl, polypropylene, polyester, latex, oils, organic solvents, waxes, lipids, esters of fatty acids, esters of sterols, long chain alcohols, myricyl palmitate, cetyl palmitate, lanolin, candelila wax, ouricury wax, sugarcane wax, retamo wax, jojoba oil, paraffin, and any combinations thereof.
- the composite material can be coated with a waterproof layer by submerging the composite material in an organic solution (e.g., solution of a water-repelling material), and/or by protecting some regions from hydration (e.g., by microcontact printing patterns of water-repelling wax materials on the surface of the composite material), and permitting it in others.
- the organic solution will have an affinity for the carbohydrate and/or protein-layer.
- the organic solution comprises wax or wax and a protein.
- the composite material can be waterproofed by depositing a layer of waterproofing material on at least one surface of the composite material.
- the composite material is coated by vapor deposition of a waterproofing material.
- the waterproofing material also can be patterned to create regions that are susceptible to water contact adjacent to regions that are not susceptible to water contact to create a composite material that varies in its mechanical properties and degradability over its surface.
- At least one surface of the composite material comprises a outer coating (e.g., one or more layers) of parylene.
- Parylene is the trade name for a variety of chemical vapor deposited poly(p-xylylene) polymers, which are USP Class VI biocompatible polymers.
- Exemplary parylenes include, but are not limited to, parylene A, AF-4, AM, C, D, E, HT, N, SF, and X. Of the three most common types of parylene (C, D and N), parylene C is the most widely used in industry.
- parylene coating can be used to create a biocompatible, waterproof coating on the composite material.
- the paralyene coating can be patterned to create regions that are hydrophobic or biocompatible adjacent to regions that are not hydrophilic or not biocompatible. Without wishing to be bound by a theory, this can create a composite material that varies in its biocompatibility, mechanical properties, or degradability over its surface.
- carbohydrate based polymer includes, but is not limited to, oligomers or polymers that contain monomers having the formula C m (H 2 O) n wherein m and n are ⁇ 3 and where in m and n can be same or different. Preferably m and n are independently 3, 4, 5, 6, or 7. Carbohydrate based polymers include, but are not limited to, compounds such as oligosaccharides, polysaccharides, glycoproteins, glycolipids and the like.
- the carbohydrate polymer comprises at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 or sugar monomers.
- the carbohydrate polymer comprises sugar monomers independently selected from the group consisting of erythrose, threose, ribose, arabinose, xylose, lyxose, ribulose, xylulose, allose, altrose, glucose, mannose, gulose, idose, galactose, galactosamine, N-acetylgalactose, glucosamine, N-acetylglucosamine, sialic acid, talose, psicose, fructose, sorbose, tagatose, fucose, fuculose, rhamonse, sedoheptulose, octose, sulfoquinovose and nonose (neuraminic acid), wherein the sugar may be optionally substituted.
- each sugar can independently have the L- or the D-conformation.
- the linkage between two sugar monomers can independently have the ⁇ - or ⁇ -configuration. Furthermore, the linkage between the two sugar can be 1->3, 1->4, 1->5, or 1->6.
- At least one (e.g., 1, 2, 3, or 4) hydroxyl of the sugar monomer is replaced by an amino group.
- the hydroxyl at position 2 of the sugar monomer is replaced by an amino group.
- the amino group can be optionally substituted with an C 1 -C 6 alkyl or an acyl group.
- Preferred C 1 -C 6 alkyl groups include methyl, ethyl, propyl, butyl, and t-butyl.
- One preferred acyl group is acetyl.
- Some carbohydrate polymer comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more) disaccharide, trisaccharide or tetrasaccharide monomers independently selected from the group consisting of sucrose, lactulose, lactose, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, ⁇ , ⁇ -Trehalose, ⁇ , ⁇ -Trehalose, sophorose, laminaribiose, gentibiose, turanose, maltulose, palatinose, gentibiulose, mannobiose, melibiose, rutinose, rutinulose, xylobiose, raffinose, melezitose, acarbose and stachyose.
- disaccharide e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more
- oligosaccharide refers without limitation to several (e.g., five to ten) covalently linked monosaccharide units.
- polysaccharide refers without limitation to many (e.g., eleven or more) covalently linked sugar units. Polysaccharides can have molecular masses ranging well into millions of daltons.
- Exemplary oligosaccharides and polysaccharides include, but are not limited to, fructooligosaccharide, galactooligosaccharides, mannanoligosaccharides, glycogen, starch (amylase, amylopectin), glycosaminoglycans (e.g., hyaluronic acid, chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate, keratin sulfate, heparin and the like), cellulose, beta-glucan (zymosan, lentinan, sizofiran), maltodextrin, inulin, levan beta (2->6), chitin, and chitosan.
- fructooligosaccharide e.g., galactooligosaccharides, mannanoligosaccharides, glycogen, starch (amylase, amylopectin), glycosaminogly
- the carbohydrate polymer is chitin or chitosan ( ⁇ -(1-4) 2-amino-2-deoxy- ⁇ -D-glucan).
- exemplary derivatives of chitosan include, but are not limited to, N-(aminoalkyl) chitosans, succinyl chitosans, quteraminated chiotosans, N-acylated chitosans (e.g., caproyl chitosan, octanoyl chitosan, myristoyl chitosan, and palmitoyl chitosan), N-methylene phosphonic chitosans, N-lauryl-N-methylene phosphonic chitosans, N-lauryl-carboxymethyl chitosans, N-alkyl-O-sulfated chitosans, thiolated chitosans (e.g., chitosan-2-iminthiolane,
- any protein that can be induced to form an ordered structure can be used in the fabrication of the composite material of the invention.
- a protein can be transformed from a random coil to a ⁇ -sheet form by treatment with heating, mechanical stretching, immersion in organic solvents, e.g., ethanol, methanol, and curing in water vapor.
- organic solvents e.g., ethanol, methanol, and curing in water vapor.
- the protein is a silk protein or an analog or a derivative thereof.
- the silk protein is fibroin.
- Silk protein can be a naturally occurring silk protein, e.g. silk extracted from silkworm cocoons, or a silk like protein or polymer.
- a number of silk like proteins and polymers are known in the art and are amenable to the present invention. See for example Asakura et al., Production and characterization of a silk-like hybrid protein, based on the polyalanine region of Samia cynthia ricini silk fibroin and a cell adhesive region derived from fibronectin, Biomaterials, 25(4): 617-624 (2004 ); Yang, M. & Kawamura, J.
- silk fibroin has excellent film-forming capabilities and is also biocompatible and acceptable for use in the human body.
- Silk fibroin films have good dissolved oxygen permeability in the wet state, similar to that of human skin, which suggests potential applications for these films in wound dressing and artificial skin systems.
- silk fibroin can be transformed from random coil to ⁇ -sheet form by treatment with heating, mechanical stretching, immersion in organic solvents, e.g., ethanol, methanol, and curing in water vapor.
- Silk fibroin can also be induced to form beta-sheets by using highly concentrated fibroin solution.
- the protein is selected from the group consisting of abductin, silk fibroin, elastin, or collagen.
- the characteristics of the composite material can be modulated, e.g., enhanced, by using a protein other than silk proteins or silk like proteins, mixture of proteins, and/or by incorporating non-protein molecules in the protein-layer.
- a protein other than silk proteins or silk like proteins, mixture of proteins, and/or by incorporating non-protein molecules in the protein-layer can be modulated, e.g., enhanced, by using a protein other than silk proteins or silk like proteins, mixture of proteins, and/or by incorporating non-protein molecules in the protein-layer.
- elastin or resilin can be used for the protein-layer, or added to carbohydrate-layer and/or protein-layer to increase elasticity.
- perlucin can be used for the protein-layer, or added to carbohydrate-layer and/or protein-layer to improve mineralization.
- the composite material comprises a material selected from the group consisting of carbon fibers, carbon nanotubes, fiberglass, small molecules, polymers, proteins, peptides, peptidomimimetics, nucleic acids, organic compounds, inorganic compounds, crystalline compounds, biological compounds, biologically active compounds, compounds having biological activity, and a biological, a pharmaceutical or a therapeutic agent, and any combinations thereof, in at least one of carbohydrate-layer or protein-layer of the composite material.
- the composite material of the invention can be prepared by preparing alternating layers of carbohydrate and protein-layers on a suitable surface.
- a carbohydrate based substrate such as a film, can first be prepared by drying a carbohydrate solution (e.g. a carbohydrate polymer solution).
- the carbohydrate based substrate is in a acid solution.
- Some exemplary acids include, but are not limited to, itaconic acid, polyitaconic acid, acontic acid, uric acid, glucuronic acid, formic acid, acetic acid, trichloroacetic acid, propionic acid, butanoic acid, 4-chlorobutanoic acid, 3-chlorobutanoic acid, 2-bromobutanoic acid, 2-chlorobutanoic acid, chlorous acid, hypochlorous acid, citric acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, ascorbic acid, Meldrum's acid, hydrofluoric acid, hydrocyanic acid, hydrogens sulfide, orthophosphoric acid, sulfurous acid, carbonic acid, conjugate acid of a weak base.
- the concentration of acid in the solution can range from about 0.1% w/v to about 10% w/v. In some embodiments, the solution comprises from about 1% w/v to about 2% w/v of the acid.
- the acid is a weak acid having an acid ionization constant (Ka) of less than 10 -2 at 25°C. In some embodiments, the acid is acetic acid.
- the prepared carbohydrate substrate can be washed and further modified and/or neutralized.
- an acidic or basic solution can be used for the modification and/or neutralization of the substrate.
- Exemplary bases include, but are not limited to, sodium hydroxide, ammonium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, strontium hydroxide, lithium hydroxide, rubidium hydroxide, sodium carbonate, and ammonia.
- concentration of base in neutralizing solution can range from about 0.1% w/v to about 10% w/v.
- the solution comprises from about 4% w/v to about 6% w/v of the base.
- the neutralizing solution is a pH buffer, e.g., a high pH carbonate buffer.
- high pH buffer is meant a buffer having a pH higher than 7, 8, 9, 10, 11, or 12 or higher.
- any remaining water molecules from the carbohydrate substrate can be removed using methods known to one of skill in the art for such purposes.
- the film can be washed with an organic solvent such as alcohol, e.g., methanol, ethanol, etc.
- an organic solvent such as alcohol, e.g., methanol, ethanol, etc.
- methods of preparing carbohydrate films are well known in the art and can be used to prepare such films. See for example, Ito, R. & Matsuo, Y. Eds. Handbook of Carbohydrate Polymers: Development, Properties and Applications, Nova Science Pub. Inc. (2010 ); and Richert et al., Langmuir, 20(2): 448-58 (2004 ).
- the carbohydrate substrate then can be coated with a layer of protein by dipping it in a protein solution.
- the carbohydrate substrate can be coated with a layer of protein by depositing a layer of protein solution on it.
- the carbohydrate to protein ratio is 1:1.5 to 1:2.5. In some embodiments, the ratio is 1:2. The ratio can be based on dry weight or moles of carbohydrate and protein added to the solution for forming the respective layers.
- the carbohydrate solution comprises from about 1% w/v to about 50% w/v of the carbohydrate polymer. In some embodiments, the carbohydrate solution comprises from about 1% w/v to about 25% w/v of the carbohydrate. In some embodiments, the carbohydrate solution comprises from about 2% w/v to about 6% w/v of the carbohydrate.
- high concentration carbohydrate solutions are used. For example, in some embodiments, the carbohydrate solution comprises from about 50% w/v to about 95% w/v of the carbohydrate. In some embodiments, the carbohydrate solution comprises from about 75% w/v to about 85% w/v of the carbohydrate.
- the protein solution comprises from about 1% w/v to about 50% w/v of the protein. In some embodiments, the protein solution comprises from about 1% w/v to about 25% w/v of the protein. In some embodiments, the protein solution comprises from about 2% w/v to about 6% w/v of the protein.
- the protein-layer can be optionally treated to induce a change in the protein structure, e.g., from fibrous to crystalline, ⁇ -helical to ⁇ -sheet, and vice versa.
- the protein-layer can be treated to induce formation of crystalline structure.
- the protein-layer can be treated to induce formation of ⁇ -sheet or similar structures.
- the protein-layer is treated to induce a ⁇ transition.
- Exemplary methods of inducing changes in protein structure include, but are limited to, using a high concentration solution of protein, heating, freezing, mechanical stretching, pressure, immersion or washing with organic solvents, e.g., ethanol, methanol, and curing in water vapor.
- the protein-layer itself can be built by a layer-by-layer design.
- the carbohydrate substrate can be coated with a first layer of protein.
- Such coated carbohydrate can then be coated with a second layer of same protein or a different protein. This process can be repeated until the total protein-layer reaches the proper thickness.
- the protein-layer can be optionally treated to induce a change in the protein structure as described above.
- the composite material has a thickness of from about 1 to about 500 ⁇ m. In some embodiments, the composite material has a thickness of from about 1 to about 250 ⁇ m, from about 1 to about 150 ⁇ m, from about 1 to about 100 ⁇ m, from about 1 to about 75, from about 1 to about 50 ⁇ m, from about 1 to about 25 ⁇ m, from about 1 to about 20 ⁇ m, from about 1 to about 15 ⁇ m, from about 1 to about 10 ⁇ m, or from about 1 to about 5 ⁇ m.
- Thickness of each carbohydrate and protein-layer in the composite material can independently range from a few angstroms to millimeters, e.g., from about 1 ⁇ to about 5 mm. In some embodiments, thickness of the each carbohydrate-layer can independently range from about 1 to about 250 ⁇ m.
- each carbohydrate-layer is selected independently from the group consisting of from about 1 to about 100 ⁇ m, from about 1 to about 75 ⁇ m, from about 1 to about 50 ⁇ m, from about 1 to about 40 ⁇ m, from about 1 to about 30 ⁇ m, from about 1 to about 25 ⁇ m, from about 1 to about 20 ⁇ m, from about 1 to about 15 ⁇ m, from about 1 to about 10 ⁇ m, and from about 1 to about 5 ⁇ m.
- all carbohydrate-layers have the same thickness. In some embodiments, at least two carbohydrate-layers have different thickness.
- the thickness of the protein-layers in the composite material can also independently range from a few angstroms to millimeters, e.g., from about 1 ⁇ to about 5 mm. In some embodiments, thickness of the each protein-layer is independently from about 1 to about 250 ⁇ m.
- each protein-layer is selected independently from the group consisting of from about 1 to about 100 ⁇ m, from about 1 to about 75 ⁇ m, from about 1 to about 50 ⁇ m, from about 1 to about 40 ⁇ m, from about 1 to about 30 ⁇ m, from about 1 to about 25 ⁇ m, from about 1 to about 20 ⁇ m, from about 1 to about 15 ⁇ m, from about 1 to about 10 ⁇ m, and from about 1 to about 5 ⁇ m.
- all protein-layers have the same thickness. In some embodiments, at least two protein-layers have different thickness.
- thickness of a protein-layer is about 0.1x to about 5x the thickness of a carbohydrate-layer. In some embodiments, thickness of a protein-layer is about 0.25x, about 0.5x, about 0.75x, about 1x, about 1.25x, about 1.5x, about 1.75x, about 2x, about 2.5x, or about 5x the thickness of a carbohydrate-layer of the composite material.
- all layers of the composite material have the same thickness. In some embodiments, at least two layers of the composite material have different thickness. The at least two layers with different thickness can be layers of the same component (e.g., carbohydrate layers or protein layers) or at least one of carbohydrate layer and at least one of protein layers.
- the composite material is formed by preparing a Chitosan film.
- the Chitosan film can be prepared by drying a solution of Chitosan in an acid, for example acetic acid, and then neutralizing the film, using for example, NaOH.
- the Chitosan film is optionally dehydrated using, for example, methanol which promotes the release of interchain water molecules.
- the resulting dried Chitosan film can become less hydratable and more brittle.
- a coating of protein, such as Fibroin for example, by dipping the Chitosan film in a fibroin water solution and allowing the resulting composite material to dry, yields a composite laminar film having significantly improved strength characteristics.
- the Chitosan film when the Chitosan film is combined with Fibroin in a range from approximately 1:1 to 4:1 (preferably 2:1.5 - 2:1) (w/w) ratio of Fibroin:Chitosan, the resulting composite material exhibits significantly greater strength characteristics than Chitosan alone.
- the composite material can be fabricated from a medium molecular weight Chitosan.
- the Chitosan material having a medium molecular weight and a high degree of deacetylation can be dissolved at 2% w/v in 1% v/v acetic acid.
- the 6ml of the resulting solution can be poured on a 9cm diameter Petri dish and the solvent evaporated at 37°C.
- the resulting film can be submerged in NaOH 4% (w/v) for a time period ranging from 5 - 15 min., for example 10 minutes, to neutralize the protonated amino groups and avoid further dissolution.
- the resulting Chitosan films can be intensely washed in deionized (DI) water to remove the remaining NaOH and then optionally dried at 37°C.
- DI deionized
- the final thickness of the Chitosan can be in the range from 7 - 13 ⁇ m, for example 10 ⁇ m.
- Silk from Bombyx Mori already degummed, available from Mielke's Fiber Arts (USA) is used to form the protein-layer.
- the silk can be washed several times in DI water before being dissolved at 10% w/v in LiBr at 80% (w/v) at 60°C for 6 hours.
- the dissolved silk can be dialyzed against water in a dialysis tube with a molecular weight cut off of 12-14kDa (VWR Scientific, USA).
- the dialysis can be carried out for 3, 4 or 5 days with constant water replacements.
- the final concentration of fibroin can be measured by weighing (XS205, Mettler Toledo, USA).
- the resulting Fibroin concentration can be in the range of 2 - 6%, for example, about 4% (w/v).
- An alternate method for producing aqueous silk fibroin solution is described in detail in WIPO Publication Number WO 2005/012606 entitled “Concentrated Aqueous Silk Fibroin Solution and Uses Thereof,".
- the Fibroin solution can be deposited on the Chitosan film immobilized at the bottom of a 9cm diameter Petri dish and dried at 37°C.
- the resulting composite film can be immersed in methanol for 25 to 35min, for example, 30min to force the beta transition of the protein (and prevent further dissolution) and washed with DI water.
- the beta transition can be induced by other inducing agents, including alcohols, organic solvents, aqueous solutions, the application of pressure and/or heat.
- Figures 1A and 1B show samples of the composite material in accordance with the invention.
- Figure 1A shows a diagram of the composite material according to one embodiment of the invention where the Chitosan film (blue) is bonded to a layer of Fibroin (green), which mimics the natural laminar structure that provides insect cuticles and crustacean exoskeletons with their novel mechanical properties.
- Figure 1B shows a picture of the composite laminar material, in this example a thin (15 ⁇ m) clear film (the bar is 2.3cm).
- a predefined microtopography of the resulting composite films can be produced by the casting the protein solution between a Polydimethoxysilane (PDMS) mold (fabricated by polymer casting on a structured Silicon surface) and the flat carbohydrate-layer or film.
- the composite film is then treated to induce a change in the protein structure, e.g., from fibrous to crystalline, ⁇ -helical to ⁇ -sheet, and vice versa.
- the protein-layer can be treated to induce formation of crystalline structure.
- the protein-layer can be treated to induce formation of ⁇ -sheet or similar structures.
- the protein-layer is treated to induce a ⁇ transition.
- the composite material can be dried and peeled from the mold.
- a predefined microtopography of the resulting composite films can be produced by the casting the Fibroin solution between a Polydimethoxysilane (PDMS) mold (fabricated by polymer casting on a structured Silicon surface) and the flat Chitosan film.
- PDMS Polydimethoxysilane
- the water can be evaporated at 37°C for several hours, and the composite material peeled off from the mold.
- the sample was methanol treated to force the beta transition and washed in DI water.
- the microtopography of the resulting composite films can be produced by depositing the protein on a structured carbohydrate film.
- the carbohydrate film can be structured by known methods, for example, by allowing a solution of carbohydrate to dry on a PDMS mold.
- the structured carbohydrate film then can be further treated as described herein to produce the structured composite material according to the invention.
- the microtopography of the resulting composite films can be produced by depositing the Fibroin protein on a structured Chitosan film.
- the Chitosan film can be structured by known methods, for example, by allowing the Chitosan in solution to dry on a PDMS mould.
- the structured Chitosan can be further treated as described herein to produce the structured composite material according to the invention.
- Figure 3 shows the casting according to the embodiments of the invention.
- Figure 3D shows the structured surface of Figure 3C in more detail.
- Samples of the dried composite material were cut in 1.5cm wide by 8 cm long stripes and tested with Instron 3342 (500N, Instron, USA). The thickness of the samples was measured with microscopy (Axio Observer, Zeiss, Germany) as the average of 5 different points of the film. The thickness measurements were also corroborated in those samples subjected to SEM analysis.
- Figure 1C shows a stress-strain curve comparing the composite material according to the invention with the individual components.
- the strength of the composite Chitosan-Fibroin laminate material at a ratio of 1:2, herein called "Shrilk” is substantially greater than either Chitosan, or the non-laminar Chitosan-Fibroin blend that was produced by mixing Chitosan and Fibroin, both in liquid phase.
- the Fibroin films are very brittle (data is not shown in Figure. 1C ), having a low breaking strength of 3.14 MPa (shown in Fig. 1C).
- Figure 1D shows the modulus of toughness and the breaking point of the compositeshrilk material and the component materials. As shown, both the modulus of toughness and breaking point of the composite laminar Shrilk material is substantially greater than either Chitosan, Fibroin or the unstructured Chitosan-Fibroin blend.
- Figures 2A shows the strength characteristics as a function of the ratio of Chitosan to Fibroin in the composite laminar material.
- Figure 2A shows that breaking strength of the composite material is significantly greater than the breaking strength of Chitosan alone when the Chitosan to Fibroin ratio is 1:2.
- Figure 2B shows an SEM image of the Chitosan-Fibroin interface within the laminar composite.
- the composite material fabricated in accordance with the invention has the same components and amounts as the blend, however, the composite material, that mimics natural structures (such as in insect cuticles), is almost ten times stronger. Moreover, surprisingly the association of the Chitosan and Fibroin in the specific configuration of "Shrilk" composite laminar material is almost twice as strong as the strongest of the components (i.e. Chitosan).
- the energy per volume which each material is able to absorb before breaking i.e. modulus of toughness, Fig. 1D ) further illustrates unexpected properties of the Chitin/protein composites in accordance with the invention.
- the composite material can absorb at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold more energy than the constituent carbohydrate film before breaking.
- the ultimate strength of 120Mpa of the composite material is twice that of Nylon and comparable to the Aluminum.
- the composite material's density is approximately 1.46g/cm3
- the Chitosan-Fibroin composite 'Shrilk' materials exhibit similar mechanical characteristics to Aluminum alloys and equivalents, but at half of the weight.
- Microlk is biocompatible and biodegradable; in certain configurations, it is also optically clear.
- the composite material can be at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold or more, stronger than the material formed from constituent carbohydrate or protein alone or a blend thereof.
- the composite material has a strength of at least 5 MPa, at least 10 MPa, at least 20 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, at least 90 MPa, at least 100 MPa or more.
- the carbohydrate layer can be in a form other than a film. Accordingly, in some embodiments, the carbohydrate layer can be in the form of a foam, sponge, fiber, mesh or a nanoscale structure.
- the composite material according to the embodiments of the invention can be fabricated into a foam-like or sponge-like material by injecting air bubbles into the carbohydrate solution as it dries, or using leachable materials (e.g., salt crystals) that can be dissolve after the foam or sponge is formed.
- the foam or sponge structure can be formed by freeze drying the carbohydrate solution. The sublimation of the solvent nucleates the bubbles that produce the porous structure of the foam or sponge.
- the size of the pores can be controlled by controlling the temperature during freeze drying, varying the solvent concentration, and the like.
- the formed carbohydrate foam or sponge can then be immersed in a solution of protein or otherwise coated with a protein solution to produce a foam-like or sponge-like structure of the composite material.
- a solution of protein or otherwise coated with a protein solution to produce a foam-like or sponge-like structure of the composite material.
- only a part or all of the carbohydrate based foam or sponge can be coated with the protein.
- porous carbohydrate materials Further information concerning the formation of porous carbohydrate materials can be found, for example, in Madihally, S.V. & Matthew, H.W.T. Porous Chitosan scaffolds for tissue engineering. Biomaterials, 20(12): 1133-1142 (1999 ); and and Xu, H.H.K& Simon, C.G. Fast setting calcium phosphate-Chitosan scaffold: mechanical properties and biocompatibility. Biomaterials, 26(12): 1337-1348 (2005 ).
- Another interesting option for forming foams is the use of high pressure CO 2 (i.e. supercritical CO 2 ) with the solid material. It mostly works by introducing CO 2 in the molecular structure by increasing the pressure, generally in the range 20Bar. When the pressure is released, the CO 2 produce cavitation of the material. This method is of increasing popularity and considered "green".
- the resulting foam or sponge can be mineralized by the introduction of crystalline materials, such as calcium carbonate, by immersing the composite material foam or sponge structure in a supersaturated solution of the crystalline material and allowing crystals to form on the surface and in the cavities.
- crystalline materials such as calcium carbonate
- the composite material according to the embodiments of the invention can be fabricated into a foam-like or sponge-like material by injecting air bubbles into the Chitosan solution as it dries, or using leachable materials (e.g., salt crystals) that can be dissolved after the foam or sponge is formed.
- the Chitosan foam sponge can be immersed or otherwise coated with a Fibroin solution to produce a foam-like structure of the composite material.
- the resulting foam can be mineralized by the introduction of crystalline materials, such as Calcium Carbonate, by immersing the composite material foam structure in a supersaturated solution of calcium carbonate in water and allowing crystals to form on the surface and in the cavities of the foam.
- an arbitrarily large amount of CaCO 3 is dissolved in water and subject to 20 psi of CO 2 for 1 - 3 days. After the pressure is released, the resulting liquid is filtered to remove the undissolved CaCO 3 . After the solution returns to room temperature, the Chitosan foam or sponge (or film) can be immersed in the CaCO 3 solution.
- the foam or sponge structure can be formed by freeze drying the Chitosan dissolved in solution.
- the sublimation of the solvent nucleates the bubbles that produce the porous structure of the foam or sponge.
- the size of the pores can be controlled by controlling the temperature during freeze drying.
- the size of the pores can be controlled by varying the concentration of the solvent.
- the Chitosan was dissolved in a 1% Acetic Acid solution as compared with the 2% Acetic Acid solution used to prepare Chitosan films. Further information concerning the formation of porous substrate materials can be found in Madihally, S.V. and H.W.T.
- Figure 5 shows samples of the composite material fabricated in a foam in accordance with the invention along side a Chitosan based foam structure in the form of a cylinder.
- Figures 6A and 6B show a mineralized foam composite material structure.
- Figure 6B shows an enlargement of the inset in Figure 6A in which the open pores of the structure are clearly visible.
- the carbohydrate can be made into fibers by electrospinning - using an electric charge to produce fibers of carbohydrate polymer from a carbohydrate solution.
- the carbohydrate fibers can be formed by injecting a solution of carbohydrates into a second solution such that the carbohydrate coagulates. The coagulate then can be extruded through a small diameter opening to control the diameter of the fiber.
- a carbohydrate solution in acid can be injected into a basic solution or vice versa.
- coagulation can be induced by modulating the salt concentration of the solution, by chemical and/or mechanical means, such as pressure, heating or cooling, shaking etc.
- the carbohydrate can be formed into fibers by rotary jet spinning as described in " Nanofiber assembly by rotary jet-spinning," Badrossamay MR, McIlwee HA, Goss JA, Parker KK, Nano Lett. 2010 Jun 9;10(6):2257-6 .
- the Chitosan can be made into fibers by electrospinning - using an electric charge to produce fibers of Chitosan from a Chitosan solution.
- fibers Chitosan can be formed by injecting a solution of Chitosan in acid (such as acetic acid) into a basic solution (such as NaOH).
- the Chitosan coagulates upon contact with the basic solution producing fibers of Chitosan.
- the coagulate can be extruded through a small diameter opening to control the diameter of the fiber.
- fiber extrusion methods such as rotary jet spinning
- rotary jet spinning e.g., Mohammad Reza Badrossamay, Holly Alice McIlwee, Josue A. Goss, Kevin Kit Parker. Nanofiber Assembly by Rotary Jet-Spinning. Nano Lett., 2010, 10 (6), pp 2257-2261 ).
- the carbohydrate-layer can be formed with a defined topography at a nanoscale.
- the protein phase then can be applied over the defined nanoscale topography.
- isotropic deposition and physical effects introduced by the topography e.g., capillarity
- Chitosan can be formed with a defined topography at a nanoscale with the protein phase applied over the structured Chitosan film.
- the result shows that the isotropic deposition and the physical effects introduced by the topography (e.g. capillarity), produce degradation of the structures in defined regions even at very low Fibroin concentrations.
- Proteins can also be used for fabricating microstructures by polymer casting. Accordingly, the microstructures can be formed by casting the protein-layer on a preformed microstructure. Additionally, the resulting composite material can be cast in a secondary shape by allowing the composite material to dry on the appropriate shape. For example, the composite material can cast into a tube by allowing the composite material to dry on a circular fixture or tube.
- the composite material can be made flexible by exposure to water, either within localized regions or in whole, and then placed on a form or fixture to dry and set the secondary shape.
- the same composite laminar material can be made to exhibit variable material properties, such as more and less flexible regions based on the absorption of more and less water, respectively. Without wishing to be bound by theory, this mimics the mechanism by which the exoskeleton of anthropods gains its variable mechanical properties.
- Fibroin is also a good material for the fabrication of microstructures by polymer casting.
- microstructures can be formed by casting the protein-layer as shown in Figures 3C and D .
- the resulting composite material can be cast in a secondary shape, such as a tube ( Fig. 3B ) by allowing composite material to dry on a circular fixture or tube.
- the composite material can be made flexible by exposure to water, either within localized regions or in whole, and then placed on a form or fixture to dry and set the secondary shape.
- the same composite laminar material can be made to exhibit variable material properties, such as more and less flexible regions based on the absorption of more and less water, respectively. This mimics the mechanism by which the exoskeleton of anthropods gains its variable mechanical properties.
- the affinity between the components can be used to assemble separate composite material layers or structured components by "gluing" them with protein, e.g. Fibroin. This process allows multiple layers of the composite material to be built-up in order to fabricate complex three dimensional biocompatible structures.
- carbohydrate components can be glued together by applying protein to dehydrated areas (or the entire surface) of the carbohydrate components and then causing a change in the protein structure, e.g., a ⁇ transition.
- Fibroin can be used to "glue" Chitosan structures.
- Chitosan components can be glued together by applying Fibroin to dehydrated areas (or the entire surface) of Chitosan components and optionally causing the beta transition of the protein, such as by the application of alcohol, pressure or heat.
- a first layer of composite material (having a first layer of protein joined to a first layer of carbohydrate) can be joined to a second layer of composite material (having a second layer of protein jointed to a second layer of carbohydrate) by "gluing" using a low concentration protein solution ("gluing solution").
- gluing solution provides less than 1:2 carbohydrate to protein ratio.
- the gluing solution comprises ⁇ 4% w/v of protein.
- the two layers of composite material can be pressed together and any air bubbles removed, such as by using a straight edge or squeegee, to provide a substantially uniform layer of protein between the carbohydrate-layers.
- the resulting multilayer composite material can be allowed to dry, for example at 37°C. Additional materials of different types can be added into the glue layer (such as carbon fibers, carbon nanotubes, or other strong materials, particulates or fibers) to further increase material properties or optimize desired behavior of the laminate material.
- Additional materials of different types can be added into the glue layer (such as carbon fibers, carbon nanotubes, or other strong materials, particulates or fibers) to further increase material properties or optimize desired behavior of the laminate material.
- a first layer of composite material (having a first layer of Fibroin joined to a first layer of Chitosan) can be joined to a second layer of composite material (having a second layer of Fibroin jointed to a second layer of Chitosan) by "gluing" using a lower concentration ( ⁇ 4% w/v) Fibroin solution that provides less than the 2:1 Fibroin to Chitosan ratio.
- the two layers of composite material can be pressed together and any air bubbles removed, such as by using a straight edge or squeegee, to provide a substantially uniform layer of Fibroin between the layers of Chitosan.
- the resulting multilayer composite material can be allowed to dry, for example at 37 C.
- Figure 3E shows an SEM cross section image of the multilayer composite material.
- additional materials of different types can be added into the glue layer (such as carbon fibers, carbon nanotubes, or other strong materials, particulates or fibers) to further increase material properties or optimize desired behavior of the laminate material.
- FIG. 2C shows the absorbance of water by the chitosan/protein composite material, providing a graph of the weight of the water saturated samples is represented against the Chitosan/Fibroin ratio.
- the composite material is hydrated.
- the term "hydrated" in reference to a composite material refers to composite material that comprises water. Accordingly, in some embodiments, the composite material is hydrated and comprises from about 5% to about 95% of water.
- the water content of a hydrated composite material can be based on the ratio of weight of water in the composite material to the total weight of the hydrated composite material. Alternatively, the water content of a hydrated composite material can be based on the ratio of weight of water in the composite material to the weight of the composite material before hydration. In some embodiments, water content of a composite material is in reference to the total amount of the carbohydrate or protein in the composite material.
- the saturation of the composite material with water can reduce the ultimate strength of the composite material by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 1-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold or more compared to the ultimate strength of the dried composite material.
- the inventors have also discovered that a significant difference between the water saturated composite material and the dry counterpart is the homogenization of the former; there is no significant mechanical difference between them. Without wishing to be bound by theory, changes introduced for the water annul other kind of interactions. Moreover, there are no notable differences in the mechanical characteristics of the composite material, carbohydrate and protein hydrated films. Again, without wishing to be bound by theory, the outstanding mechanical characteristics of the composite material result from the different mechanical properties of the components.
- the saturation of the chitosan/fibroin composite material with water reduced the ultimate strength to an average value of 3.5Mpa, which is more than 30 times below that obtained for the dry material.
- the energy absorbed prior to yielding is only reduced by a factor of two; the remaining energy is stored as a significant increase of the elasticity, up to a 23% ultimate strain of its original size, in contrast with the 2.7% for the composite material when dry as shown in Figure 2D .
- IR spectra were obtained with a resolution of 2cm -1 between the 4000 and 500cm -1 (Vertex 70, Bruker, Germany) and analyzed with Essential FTIR (Operant LLC, USA).
- the Fibroin on composite material FTIR data was obtained by employing the single beam spectra from a Chitosan film as background signal before the Fourier transformation.
- the compositeshrilk material shows an IR absorption spectrum very similar to the sum of Chitosan ( Fig. 4A , black) and Fibroin ( Fig 4C , black).
- Fig. 4A shows an IR absorption spectrum very similar to the sum of Chitosan
- Fig 4C shows an IR absorption spectrum very similar to the sum of Chitosan ( Fig. 4A , black) and Fibroin ( Fig 4C , black).
- the amine II band with respect the Chitosan (from 1562 to 1536cm -1 ), even with a very thin Fibroin layer.
- This band relates to the mixing between the N-H bending mode, from the amide and amine, and the C-N stretching mode. Therefore, the main interaction between both phases appears to be made through the Nitrogen atom in the number 2 position of the Chitin/Chitosan saccharide ring.
- the interaction between the different components in the composite material appears to be restricted to the interface, with the new bonds being screened by signals from the bulk material.
- the Fibroin spectra in the composite material is shown in grey in Figure 4C , compared with a single beam spectrum produced by a Chitosan film as background.
- a comparison with the pure Fibroin films demonstrates an apparent loss in the region around the 3454cm -1 (stretching of the free NH), which support the hypothesis of new bonds being formed with the initially free NH.
- the modification of the Amide II band already mentioned because the lost in the absorption band at 1560cm -1 )
- there is a significant decrease in the 1417cm -1 band in addition to the modification of the Amide II band already mentioned (because the lost in the absorption band at 1560cm -1 ).
- the composite material fabricated in accordance with the present invention is an organic composite laminate material made of biodegradable and biocompatible materials with the strength of the Aluminum alloys but with one half its density.
- the composite material can be used in many biomedical applications.
- the composite material can be used in prosthetic devices, tissue engineering scaffolds, wound healing devices and components as well as a replacement for plastics and other synthetic or inorganic materials.
- the stiffness or flexibility of the material can enable it to be used in place of a wide range of tissue types and functions, for example as a scaffold or other prosthetic component.
- the porous nature of the foam and sponge structural embodiments enables embodiments of the invention to be used for drug and therapeutic agent delivery by incorporating the agent in the pores during or after the fabrication process.
- the composite material can also-be used for non-medical applications, e.g. for industrial applications.
- the composite material can be used anywhere a lightweight high strength material is needed, such as in the automotive (e.g., hybrid vehicles, electric vehicles, and racing vehicles) and aeronautical industries.
- the composite material can also be used to replace plastics used in the food industry, such as for containers and bottles.
- the composite material can be used to manufacture consumer goods including, but not limited to, storage containers, luggage, backpacks, tents, clothing, and disposable trash bags.
- Other exemplary uses of the composite material can include, but are not limited to, bullet proof windows, shatter proof windows, boat sails, parachutes, artillery storage, tires, vehicle bumpers, crash barriers, and road maintenance equipment (e.g., pylons).
- the composite material can be used in manufacturing of components for electronic devices, such as laptops.
- the composite material of the present invention has many applications including, for example, drug delivery systems, tissue engineered materials or other biomedical devices. All of the composites described herein can be easily functionalized with drugs, antibiotics, cell responses molecules, dyes, enzymes and other small and large molecules, with retention of function.
- the embodiments of the present invention thus provides for composites that may be suitable for a tissue engineered constructs that can be used for defect and organ repair, organ replacement or regeneration strategies that may benefit from these modified silk materials.
- a composite of the invention can be used for organ repair, organ replacement or regeneration strategies including, but not limited to, spinal disc, cranial tissue, dura, nerve tissue, liver, pancreas, kidney, bladder, spleen, cardiac muscle, skeletal muscle, tendons, ligaments, cornea tissues, and breast tissues.
- a composite of the invention can be used for defect repair such as hernial repair and wound closure and repair to medical applications.
- a composite of the material can be used as a full or partial prosthesis and in plastic surgery applications, such as to support reconstruction and to reduce scarring.
- any type of cell can be added to the tissue-engineered construct for culturing and possible implantation, including cells of the muscular and skeletal systems, such as chondrocytes, fibroblasts, muscle cells and osteocytes, parenchymal cells such as hepatocytes, pancreatic cells (including Islet cells), cells of intestinal origin, and other cells such as nerve cells, bone marrow cells, skin cells, pluripotent cells and stem cells (including, e.g., embyonic stems, adult stem cells, and induced pluripotent stem(iPS) cells), and combination thereof, either as obtained from donors, from established cell culture lines, or even before or after molecular genetic engineering.
- Pieces of tissue can also be used, which may provide a number of different cell types in a single structure.
- the composites can be modified to contain at least one active agent.
- the agent may be mixed with a carbohydrate and/or protein solution prior to forming the composite material, or loaded into the composite material or a portion thereof after it is formed.
- the agent can also be covalently linked with carbohydrate or protein-layers.
- the agent can be linked with the carbohydrate or protein before formation of the composite material.
- the agent can be covalently linked to the carbohydrate or protein-layer after formation of the composite material. Accordingly, the agent can be directly linked with the carbohydrate or protein-layer with a bond or through an intermediate linker.
- active agents that can be used in conjunction with the composite material of the present invention is vast and can include small molecules, polymers, proteins, peptides, peptidomimimetics, nucleic acids, organic compounds, inorganic compounds, biological compounds, biologically active compounds, compounds having biological activity.
- the active agent may be a therapeutic agent or biological material, such as cells (including stem cells), proteins, peptides, nucleic acids (DNA, RNA, plasmids, siRNA, antisense oligonucleotides, decoy oligonucleotides, microRNA, aptamers, and ribozymes), nucleic acid analogues, nucleotides, oligonucleotides or sequences, peptide nucleic acids, antibodies, hormones, hormone antagonists, growth factors or recombinant growth factors and fragments and variants thereof, cytokines, or enzymes, antibiotics, viruses, antivirals, toxins, prodrugs, chemotherapeutic agents, small molecules, drugs and combinations thereof.
- cells including stem cells
- proteins such as cells (including stem cells), proteins, peptides, nucleic acids (DNA, RNA, plasmids, siRNA, antisense oligonucleotides, decoy oligonucleotides
- Some exemplary active agents suitable for modifying the composite materials of the present invention includes cells (including stem cells), erythropoietin (EPO), YIGSR peptides, glycosaminoglycans (GAGs), hyaluronic acid (HA), integrins, selectins and cadherins; analgesics and analgesic combinations; steroids; antibiotics; insulin; interferons ⁇ and ⁇ ; interleukins; adenosine; chemotherapeutic agents (e.g., anticancer agents); tumor necrosis factors ⁇ and ⁇ ; antibodies; cell attachment mediators, such as RGD or integrins, or other naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, cytotoxins, prodrugs, immunogens, or lipoproteins.
- EPO erythropoietin
- YIGSR peptides glycosaminoglycans
- GAGs glycosaminogly
- exemplary therapeutic agents include, but are not limited to, those found in Harrison's Principles of Internal Medicine, 13th Edition, Eds. T.R. Harrison et al. McGraw-Hill N.Y., NY ; Physicians Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co. ; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990 ; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990 ; current edition of Goodman and Oilman's The Pharmacological Basis of Therapeutics ; and current edition of The Merck Index.
- Other material to be embedded in composite materials can include liposomes and related systems for delivery of genetic materials; peptides and proteins to active cellular signaling cascades; peptides and proteins to promote mineralization or related events from cells; adhesion peptides and proteins to improve film-tissue interfaces; antimicrobial peptides; proteins and related compounds; and carbohydrates, including, for example, glycosaminoglycans and proteoglycans.
- one or more active agents can be used to modify the composite material. Accordingly, when using the composite of the present invention as a platform to support biological material such as cells, it can be desirable to add other materials to promote the growth of the agent, promote the functionality of the agent after it is released from the composite, or increase the agent's ability to survive or retain its efficacy during the processing period.
- Exemplary materials known to promote cell growth include, but not limited to, cell growth media, such as Dulbecco's Modified Eagle Medium (DMEM), fetal bovine serum (FBS), non-essential amino acids and antibiotics, and growth and morphogenic factors such as fibroblast growth factor (e.g., FGF 1-9), transforming growth factors (TGFs), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet derived growth factor (PDGF), insulin-like growth factor (IGF-I and IGF-II), bone morphogenetic growth factors (e.g., BMPs 1-7), bone morphogenetic-like proteins (e.g., GFD-5, GFD-7, and GFD-8), transforming growth factors (e.g., TGF- ⁇ , TGF- ⁇ I-III), nerve growth factors, and related proteins.
- Growth factors are known in the art, see, e.g., Rosen & Thies, Cellular & Mol. Basis Bone Formation & Repair (
- compositions, methods, and respective component(s) thereof that are essential to the invention, yet open to the inclusion of unspecified elements, whether essential or not.
- the terms “comprising” and “comprises” include the terms “consisting of' and “consisting essentially of.”
- the term "consisting essentially of' refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.
- compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.
- “decrease”, “reduced”, “reduction”, “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount.
- “reduced”, “reduction” or “decrease” or “inhibit” means a decrease by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g. absent level as compared to a reference sample), or any decrease between 10-100% as compared to a reference level.
- the terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
- statically significant refers to statistical significance and generally means a two standard deviation (2SD) below normal, or lower, concentration of the marker.
- 2SD two standard deviation
- the term refers to statistical evidence that there is a difference. It is defined as the probability of making a decision to reject the null hypothesis when the null hypothesis is actually true. The decision is often made using the p-value.
- the terms “effective” and “effectiveness” includes both pharmacological effectiveness and physiological safety.
- Pharmacological effectiveness refers to the ability of the treatment to result in a desired biological effect in the patient.
- Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (often referred to as side-effects) resulting from administration of the treatment.
- Less effective means that the treatment results in a therapeutically significant lower level of pharmacological effectiveness and/or a therapeutically greater level of adverse physiological effects.
- a "subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
- Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
- Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents.
- the subject is a mammal, e.g., a primate, e.g., a human.
- the terms, "patient” and “subject” are used interchangeably herein.
- the terms, "patient” and “subject” are used interchangeably herein.
- a subject can be male or female.
- the subject is a mammal.
- the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with autoimmune disease or inflammation.
- the methods and compositions described herein can be used to treat domesticated animals and/or pets.
- Transglutaminase in powder form was applied at about 20mg/cm 2 on the tissue and a hydrated film (either shrilk or a chitosan film as comparative example) was contacted with the tissue. After 30 minutes of bonding at room temperature, the sample was subjected to a peel test. Results of the peel test are shown in Fig. 23 . The inventors discovered that the either side of a shrilk film (carbohydrate layer or the protein layer) can be contacted with the tissue for bonding.
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Claims (16)
- Un matériau laminaire composite comprenant une couche de glucides et une couche de protéines, dans lequel le rapport glucide / protéine est compris entre 1 : 1,5 et 1 : 2,5 et dans lequel le glucide est la chitine ou le chitosane et la protéine est la soie fibroïne, élastine, abductine ou collagène.
- Le matériau laminaire composite selon la revendication 1, dans lequel la couche d'hydrate de carbone comprend un film, une fibre, une éponge, une maille, une mousse ou une structure à l'échelle nanométrique.
- Le matériau laminaire composite selon l'une quelconque des revendications 1 et 2, dans lequel le matériau composite comprend un matériau choisi dans le groupe constitué de fibres de carbone, nanotubes de carbone, fibre de verre, petites molécules, polymères, protéines, peptides, peptidomimimétiques, acides nucléiques, composés organiques, composés inorganiques, composés cristallins, composés biologiques, composés biologiquement actifs, composés ayant une activité biologique, et un agent biologique, pharmaceutique ou thérapeutique, et toute combinaison de ceux-ci, dans au moins une couche de carbohydrate ou de protéine.
- Le matériau laminaire composite selon la revendication 3, dans lequel le matériau est(a) dans la couche de glucides ; par exemple lié de manière covalente à la couche de carbohydrate ; ou(b) dans la couche protéique, par exemple liée de manière covalente à la couche protéique.
- Un procédé de formation d'un matériau laminaire composite comprenant :
fournir une couche de carbohydrate et mettre en contact la couche de glucide avec une solution de protéines, dans lequel le rapport glucide / protéine est compris entre 1 : 1,5 et 1 : 2,5 et dans lequel le glucide est la chitine et la fibroïne de soie, l'élastine, l'abduction ou le collagène. - Le matériau laminaire composite selon l'une quelconque des revendications de 1 à 4, ou procédé selon la revendication 5, dans lequel le rapport des hydrates de carbone à la protéine est de 1 : 2.
- Le matériau laminaire composite selon l'une quelconque des revendications de 1 à 4 et 6, ou procédé selon la revendication 5 ou 6, dans lequel l'hydrate de carbone est le chitosane.
- Le matériau laminaire composite selon l'une quelconque des revendications de 1 à 4, 6 et 7, ou procédé selon l'une quelconque des revendications 5 à 7, dans lequel la protéine est de la fibroïne de soie.
- Le matériau laminaire composite selon l'une quelconque des revendications de 1 à 4, 6 et 7 ou procédé selon l'une quelconque des revendications 5 à 7, dans lequel la protéine est le collagène.
- Le procédé selon l'une quelconque des revendications de 5 à 9, dans lequel la couche d'hydrate de carbone est formée en déshydratant une solution d'une matière à base de glucide, par exemple une solution d'une matière à base d'hydrate de carbone qui comprend un acide.
- Le procédé selon l'une quelconque des revendications de 5 à 10, comprenant en outre : introduire un matériau support choisi dans le groupe constitué de nanotubes de carbone, fibre de verre, petites molécules, polymères, protéines, peptides, peptidomimimétiques, acides nucléiques, composés organiques, composés inorganiques, cristallins des matériaux, composés biologiques, composés biologiquement actifs, composés ayant une activité biologique, et un agent biologique, pharmaceutique ou thérapeutique, et toutes combinaisons de ceux-ci, avec le matériau composite.
- Le procédé selon l'une quelconque des revendications de 5 à 11, comprenant :
la dissolution d'un matériau à base de chitine dans une solution acide ; former une structure à base de chitine du matériau à base de chitine par évaporation du solvant ; traiter la structure à base de chitine avec une solution de base pour neutraliser les groupes amino protonés ; laver la structure à base de chitine ; déshydrater facultativement la structure à base de chitine ; appliquer une solution de protéine à la structure à base de chitine pour produire un matériau composite ayant au moins une couche de protéine sur la structure à base de chitine ; sécher la couche de protéine sur la structure à base de chitine ; et traiter le matériau composite avec une solution à base d'alcool pour induire une transition bêta de la protéine. - Une composition de matière pouvant être formée par le procédé de l'une quelconque des revendications de 5 à 12.
- Un produit antiadhésif comprenant la composition de matière selon la revendication 13, dans lequel le produit est un dispositif prothétique, un échafaudage d'ingénierie tissulaire ou un dispositif d'administration de médicament.
- Un matériau comprenant la composition de matière selon la revendication 13, dans lequel le matériau est un matériau implantable, un matériau comprenant des minéraux ou des matériaux cristallins, un film mince transparent, un matériau multi-stratifié, un matériau multi-stratifié comprenant des composants supplémentaires à fournir des propriétés mécaniques adaptées, un matériau comprenant un matériau de revêtement hydrofuge, un matériau comprenant des régions variables d'un matériau de revêtement hydrofuge pour fournir des régions avec une flexibilité variable.
- Le matériau laminaire composite selon la revendication 1 ou le procédé selon la revendication 5, dans lequel le glucide est le chitosane et la protéine est la fibroïne de soie, et dans lequel le rapport chitosane / fibroïne de la soie est de 1 : 2.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37805610P | 2010-08-30 | 2010-08-30 | |
PCT/US2011/049702 WO2012030805A2 (fr) | 2010-08-30 | 2011-08-30 | Matériau composite à base de chitine de grande résistance et son procédé de fabrication |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2611471A2 EP2611471A2 (fr) | 2013-07-10 |
EP2611471A4 EP2611471A4 (fr) | 2015-04-22 |
EP2611471B1 true EP2611471B1 (fr) | 2018-10-03 |
Family
ID=45773473
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP11822477.3A Active EP2611471B1 (fr) | 2010-08-30 | 2011-08-30 | Matériau composite à base de chitine de grande résistance et son procédé de fabrication |
Country Status (9)
Country | Link |
---|---|
US (2) | US9433698B2 (fr) |
EP (1) | EP2611471B1 (fr) |
JP (3) | JP6053682B2 (fr) |
KR (1) | KR20130138763A (fr) |
CN (1) | CN103200971B (fr) |
AU (1) | AU2011296133B2 (fr) |
CA (1) | CA2809372A1 (fr) |
SG (2) | SG188273A1 (fr) |
WO (1) | WO2012030805A2 (fr) |
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Publication number | Publication date |
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US20160296665A1 (en) | 2016-10-13 |
EP2611471A2 (fr) | 2013-07-10 |
CA2809372A1 (fr) | 2012-03-08 |
SG188273A1 (en) | 2013-04-30 |
CN103200971A (zh) | 2013-07-10 |
JP2018171515A (ja) | 2018-11-08 |
AU2011296133A1 (en) | 2013-03-14 |
WO2012030805A3 (fr) | 2012-07-05 |
WO2012030805A2 (fr) | 2012-03-08 |
SG10201607262PA (en) | 2016-10-28 |
JP6433465B2 (ja) | 2018-12-05 |
JP6053682B2 (ja) | 2016-12-27 |
US9433698B2 (en) | 2016-09-06 |
KR20130138763A (ko) | 2013-12-19 |
US20130287836A1 (en) | 2013-10-31 |
AU2011296133B2 (en) | 2015-12-17 |
JP2017012762A (ja) | 2017-01-19 |
JP2013536734A (ja) | 2013-09-26 |
EP2611471A4 (fr) | 2015-04-22 |
CN103200971B (zh) | 2015-09-30 |
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